Novel forms of pravastatin sodium

ABSTRACT

New polymorphic forms of pravastatin sodium are provided. Each of the new forms is selectively obtained by crystallization from different solvent systems, each solvent system having a protic component, and by controlling the rate of crystallization through temperature. The new polymorphic forms are suitable for use as active substances of pharmaceutical dosage forms for reduction of serum cholesterol levels in the bloodstream.

RELATED APPLICATION

[0001] This application claims the benefit under 35 U.S.C. § 119(e) ofU.S. Provisional Patent Application No. 60/170,685, filed Dec. 14, 1999and U.S. Provisional Patent Application No. 60/190,649, filed Mar. 20,2000.

FIELD OF THE INVENTION

[0002] The present invention relates to statins, and more particularlyto novel polymorphic forms of pravastatin sodium.

BACKGROUND OF THE INVENTION

[0003] Pravastatin is a member of the class of pharmaceutical compoundscalled statins. Statins currently are the most effective treatment forlowering serum cholesterol levels in patients with atherosclerosis andhypercholesteremia. Pravastatin is the common medicinal name of thechemical compound[1S-[1α(β*,δ*)2α,6α,8β(R*),8aα]]-2,6,7,8,8a-hexahydro-β,δ,6-trihydroxy-2-methyl-8-(2-methyl-1-oxobutoxy)-1-naphthalene-heptanoicacid. (CAS Registry No. 81093-37-0) The molecular structure ofpravastatin is represented by Formula (I). “Pravastatin sodium” isdefined as the monosodium salt of pravastatin, whether hydrated oranhydrous, solvated or unsolvated.

[0004] According to U.S. Pat. No. 4,346,227, incorporated herein byreference, pravastatin is reported as having been first isolated as ametabolite of compactin by M. Tanaka et al. during a study of compactinmetabolism. The '227 patent discloses the isolation of pravastatin inits lactone form, as the methyl ester of the free carboxylic acid and asthe monosodium salt of the free carboxylic acid (“pravastatin sodium”).Pravastatin sodium was analyzed by nuclear magnetic resonancespectroscopy, infrared (“IR”) spectroscopy, ultraviolet spectroscopy andthin layer chromatography. Pravastatin sodium was analyzed in solid formby IR spectroscopy using the conventional technique of co-mixing withpotassium bromide (“KBr”) and then compressing to form a KBr window orpellet. The IR spectrum of the pravastatin sodium obtained by absorptionbands at 3400, 2900, 1725, 1580 cm⁻¹. All other spectral measurementsare repeated on pravastatin sodium in solution.

[0005] The present invention relates to new crystal forms of pravastatinsodium and compositions containing them. Polymorphism is the property ofsome molecules and molecular complexes to assume more than onecrystalline form in the solid state. A single molecule may give rise toa variety of crystal forms (also called “polymorphs”) having distinctphysical properties. The existence of more than one crystal form can bedetermined in a laboratory by comparison of the angles at which X-rayradiation reflected from the forms undergoes constructive interferenceand by comparing the absorptions of incident infrared radiation atdifferent wavelengths. The former technique is known as X-raydiffraction spectroscopy and the angles at which constructiveinterference occurs are known as reflections.

[0006] The differences in the physical properties of polymorphs resultfrom the orientation and intermolecular interactions of adjacentmolecules (complexes) in the bulk solid. Accordingly, polymorphs aredistinct solids sharing the same molecular formula yet having distinctadvantageous and/or disadvantageous physical properties compared toother forms in the polymorph family.

[0007] One of the most important physical properties of a polymorphicpharmaceutical compound is the solubility of each of its forms inaqueous solution, particularly the solubility in gastric juices of apatient. Other important properties relate to the ease of processing theform into pharmaceutical dosages, such as the tendency of a powdered orgranulated form to flow and the surface properties that determinewhether crystals of the form will adhere to each other when compactedinto a tablet.

SUMMARY OF THE INVENTION

[0008] The present invention is directed to new polymorphic forms ofpravastatin sodium.

[0009] These forms are designated Form A, Form B, Form C, Form D, FormE, Form F, Form G, Form H, Form H1, Form I, Form J, Form K and Form L.The invention is also directed to methods of making each of thepravastatin sodium polymorphs.

BRIEF DESCRIPTION OF THE DRAWINGS

[0010]FIG. 1 is a characteristic powder X-ray diffraction pattern ofpravastatin sodium Form A.

[0011]FIG. 2 is a characteristic infrared absorption spectrum ofpravastatin sodium Form A.

[0012]FIG. 3 is a characteristic powder X-ray diffraction pattern ofpravastatin sodium Form B.

[0013]FIG. 4 is a characteristic infrared absorption spectrum ofpravastatin sodium Form B.

[0014]FIG. 5 is a characteristic powder X-ray diffraction pattern ofpravastatin sodium Form C.

[0015]FIG. 6 is a characteristic infrared absorption spectrum ofpravastatin sodium Form C.

[0016]FIG. 7 is a characteristic powder X-ray diffraction pattern ofpravastatin sodium Form D.

[0017]FIG. 8 is a characteristic infrared absorption spectrum ofpravastatin sodium Form D.

[0018]FIG. 9 is a characteristic powder X-ray diffraction pattern ofpravastatin sodium Form E.

[0019]FIG. 10 is a characteristic infrared absorption spectrum ofpravastatin sodium Form E.

[0020]FIG. 11 is a characteristic powder X-ray diffraction pattern ofpravastatin sodium Form F.

[0021]FIG. 12 is a characteristic infrared absorption spectrum ofpravastatin sodium Form F.

[0022]FIG. 13 is a characteristic powder X-ray diffraction pattern ofpravastatin sodium Form G.

[0023]FIG. 14 is a characteristic powder X-ray diffraction pattern ofpravastatin sodium Form H.

[0024]FIG. 15 is a characteristic powder X-ray diffraction pattern ofpravastatin sodium Form H1.

[0025]FIG. 16 is a characteristic powder X-ray diffraction pattern ofpravastatin sodium Form I.

[0026]FIG. 17 is a characteristic powder X-ray diffraction pattern ofpravastatin sodium Form J.

[0027]FIG. 18 is a characteristic powder X-ray diffraction pattern ofpravastatin sodium Form K.

[0028]FIG. 19 is a characteristic powder X-ray diffraction pattern ofpravastatin sodium Form L.

DETAILED DESCRIPTION OF THE INVENTION

[0029] We have discovered new polymorphic forms of pravastatin sodiumthat can be distinguished from the known amorphous pravastatin sodiumand from each other by their powder X-ray reflections and their infraredabsorption spectra.

[0030] All powder X-ray diffraction patterns were obtained by methodsknown in the art using a Philips X-ray powder diffractometer, withgoniometer model 1050/70, at scanning speed of 2° min.⁻¹. Copperradiation of λ=1.5418 Å was used.

[0031] The infrared spectrum was obtained in a Nujol mull using a PerkinElmer Paragon 1000 FT-IR spectrometer at 4 cm⁻¹ resolution with 16scans. The characteristic infrared absorption bands of the novel formsof pravastatin sodium will not necessarily be observed in the IRspectrum of a sample that has been dissolved, as for example inchloroform or carbon tetrachloride, for IR analysis. That is: some IRbands may be characteristic of pravastatin in the solid state; othersare characteristic of pravastatin sodium whether in the solid orsolution phase.

[0032] Pravastatin crystal forms show DSC curves with multipleendothermic and exothermic events due to water desorption and phasetransitions. The melting peak observed in all forms except form B is inthe range of about 174-176° C. Form B has a melting point at about 187°C.

[0033] Pravastatin crystal forms exhibit hygroscopic behavior. The wateruptake at 80% relative humidity after 1 week was up to about 15%. Afterexposure at 100% relative humidity, all the forms of pravastatin sodiumtransform to Form C with about 30% relative humidity. It was also foundthat all the crystal forms, except Form B, were transformed to Form D byheating at 120° C. for 2 hours.

[0034] Characteristics of Pravastatin Sodium Polymorphs

[0035] Pravastatin sodium Form A is characterized by reflections in thepowder X-ray diffraction pattern at 3.9, 4.5, 6.2, 7.2, 8.6, 9.2, 10.0,11.6, 12.0, 17.0 and 20.0±0.2 degrees, detected at reflection angle 2θ.The diffraction pattern is reproduced in FIG. 1. Of these, thereflections at 3.9, 4.5, 6.2, and 7.2±0.2 degrees are especiallycharacteristic. Form A may also be distinguished by its infraredabsorption spectrum which is shown in FIG. 2 obtained in a Nujol mull.Form A has characteristic; absorption bands at 686, 826, 842, 864, 917,939, 965, 1013, 1040, 1092, 1111, 1156, 1184, 1265, 1310, 1330, 1576 and1726, ±2 cm⁻¹.

[0036] Pravastatin sodium Form B is distinguished by reflections in thepowder X-ray diffraction pattern that are observed at 3.6, 6.1, 6.6,9.0, 9.6, 10.1, 16.4, 16.8 and 18.6±0.2 degrees detected at thereflection angle 2θ. The diffraction pattern is reproduced in FIG. 3.The reflections at 3.6, 6.1, 6.6, 9.0, 9.6, 10.1 and 18.6±0.2 degreesare the most intense and in that sense the most characteristic, thereflections at 3.6, 6.1 and 6.6±0.2 degrees being the most intense ofall. Form B may further be distinguished by its IR spectrum, provided asFIG. 4, obtained from a Nujol mull. Absorption bands are observed at614, 692, 739, 824, 842, 854, 868, 901, 914, 936, 965, 1011, 1028, 1039,1072, 1091, 1111, 1129, 1149, 1161, 1185, 1232, 1245, 1318, 1563, 1606,1711 and 1730±2 cm⁻¹.

[0037] Pravastatin sodium Form C may be distinguished by reflections inthe powder X-ray diffraction pattern that are observed at about 4.8,7.6, 8.6, 10.0, 11.8, 12.4, 13.0, 15.5, 16.0, 17.4, 17.9, 18.4, 19.7,21.0, 21.8 and 22.8±0.2 degrees, detected at reflection angle 2θ. Thereflections observed at 4.8, 7.6, 8.7, 10.0, 13.0, 16.0, 17.4 and19.7±0.2 degrees are characteristic and, of these, the reflections at4.8, 10.0, 13.0, 16.0 and 17.4±0.2 degrees are especiallycharacteristic. The diffraction pattern is reproduced in FIG. 5. Form Cmay further be distinguished by its IR spectrum, provided as FIG. 6,obtained from a Nujol mull. Absorption bands of pravastatin sodium FormC are observed at 742, 829, 851, 870, 926, 940, 964, 1013, 1038, 1078,1090, 1146, 1166, 1174, 1194, 1257, 1268, 1313, 1328, 1567 and 1728±2cm⁻¹.

[0038] Pravastatin sodium Form D may be distinguished from the otherforms of crystalline and amorphous pravastatin sodium by reflections inthe powder X-ray diffraction pattern that are observed at 3.6, 6.3, 9.8and 17.1±0.2 degrees, detected at reflection angle 2θ. The diffractionpattern is reproduced in FIG. 7. Form D may further be distinguished byits IR spectrum, provided as FIG. 8, obtained from a KBr window usingthe same equipment and methodology as was used to obtain the IR spectrumof Form A. Characteristic absorption bands of pravastatin sodium Form Dare observed at 824, 843, 854, 914, 939, 965, 1013, 1041, 1079, 1091,1157, 1186, 1266, 1566, 1606 and 1728±2 cm⁻¹.

[0039] Pravastatin sodium Form E exhibits reflections in the powderX-ray diffraction pattern at about 4.6, 9.2, 10.3, 11.2, 12.1, 16.6,18.3 and 20.6±0.2 degrees, detected at a reflection angle of 2θ. Form Eis readily distinguished from the other forms of crystalline andamorphous pravastatin sodium by the reflections at 4.6, 9.2, 10.3, 12.1,16.6, 18.3 and 20.6±0.2 degrees, the reflections at 10.3, 12.1 and 16.6degrees being especially characteristic of Form E. The diffractionpattern is reproduced in FIG. 9. Form E may further be distinguished byits IR spectrum, provided as FIG. 10, obtained from a Nujol mull.Characteristic absorption bands of pravastatin sodium Form E areobserved at 781, 829, 853, 939, 964, 1016, 1043, 1078, 1158, 1179, 1266,1300, 1329, 1401, 1573 and 1727±2 cm⁻¹.

[0040] Pravastatin sodium Form F may be distinguished from the otherforms of pravastatin sodium by the reflection in the powder X-raydiffraction pattern that occurs at about 4.6±0.2 degrees, detected atreflection angle 2θ. The absence of other diffraction peaks points tothe amorphous nature of this form. The diffraction pattern is reproducedin FIG. 11. Form F may be distinguished by its IR spectrum, provided asFIG. 12, obtained from a KBr window. Absorption bands are observed at781, 829, 853, 939, 964, 1016, 1043, 1079, 1157, 1181, 1265, 1300, 1330,1400, 1576 and 1727±2 cm⁻¹.

[0041] Pravastatin sodium Form G may be distinguished by reflections inthe powder X-ray diffraction pattern that are observed at about 4.5,9.2, 10.0, 12.2, 16.0, 16.5, 17.6, 18.6, 19.5, 20.5, and 22.8±0.2degrees, detected at reflection angle 2θ. The diffraction pattern isreproduced in FIG. 13. Pravastatin sodium Form G has a DSC scancharacterized by two endotherms at about 165° and 173° C. followed bydecomposition.

[0042] Pravastatin sodium Form H may be distinguished by reflections inthe powder X-ray diffraction pattern that are observed at about 3.5,5.9, 9.0, 10.1, 11.7, 12.1, 14.7, 17.0 19.0, 19.9, 20.6, 21.8 and22.9±0.2 degrees, detected at reflection angle 2θ. Of these, the peaksat 3.5, 5.9, 9.0, 10.1 and 17.0±0.2 degrees are particularly diagnostic.The diffraction pattern is reproduced in FIG. 14.

[0043] Pravastatin sodium Form HI may be distinguished from the otherforms of crystalline and amorphous pravastatin sodium by reflections inthe powder X-ray diffraction pattern that are observed at about 3.5,5.9, 6.8, 8.9, 10.1, 11.7, 12.3, 13.3, 14.8, 17.6, 18.8, 20.0, 20.8, and22.9±0.2 degrees, detected at reflection angle 2θ. Of these, the peaksat 3.5, 5.9, 8.9, 10.1, 17.6, 18.8 and 20.8±0.2 degrees are particularlydiagnostic. The diffraction pattern is reproduced in FIG. 15.

[0044] Pravastatin sodium Form I may be distinguished from the otherforms of crystalline and amorphous pravastatin sodium by reflections inthe powder X-ray diffraction pattern that are observed at about 4.4,5.2, 5.8, 6.5, 7.5, 8.3, 9.0, 9.8, 10.2, 11.2, 13.2, 14.0, 16.5, 17.5,18.3, 18.7, 19.5, 20.5, 21.5 and 23.0±0.2 degrees, detected atreflection angle 2θ. Of these, the peaks at 4.4, 5.2, 5.8, 6.5, 9.0,13.2, and 14.0±0.2 degrees are particularly diagnostic. The diffractionpattern is reproduced in FIG. 16.

[0045] Pravastatin sodium Form J may be distinguished from the otherforms of crystalline and amorphous pravastatin sodium by reflections inthe powder X-ray diffraction pattern that are observed at about 3.3,3.8, 6.0, 6.8, 7.5, 8.8, 9.3, 10.2, 11.2, 11.7, 13.5, 13.9, 14.5, 15.6,16.3, 17.7, 18.1, 18.7, 19.5, 20.0, 20.4, 21.7, 22.3, 24.2, and 26.1±0.2degrees, detected at reflection angle 2θ. Of these, the peaks at 3.8,6.0, and 16.3±0.2 degrees are particularly diagnostic. The diffractionpattern is reproduced in FIG. 17.

[0046] Pravastatin sodium Form K may be distinguished by reflections inthe powder X-ray diffraction pattern that are observed as a broad peakbetween 15 and 25 as well as peaks at 4.1, 6.8 and 10.2 degrees measuredat reflection angle 2θ. The diffraction pattern is reproduced in FIG.18.

[0047] Pravastatin sodium Form L may be distinguished from the otherforms of crystalline and amorphous pravastatin sodium by reflections inthe powder X-ray diffraction pattern that are observed at about 4.5,5.0, 9.0, 10.1, 12.3, 13.4, 15.0, 16.6, 17.6, 18.5 19.5, 20.2, 21.2 and22.7±0.2 degrees, detected at reflection angle 2θ. Of these, the peaksat 16.6, 17.6, and 18.5±0.2 degrees are particularly diagnostic. Thediffraction pattern is reproduced in FIG. 19.

[0048] Procedures for Crystallizing Polymorphs of Pravastatin Sodium

[0049] It will be appreciated by those skilled in the art ofcrystallization that attainment of a particular crystalline form of acompound is highly dependent upon exacting control of conditions. Theseconditions include, among other parameters, the composition of thesolvent system employed, the pH of the solvent system, the temperatureprofile and the form of any crystals that are added to inducecrystallization from a supersaturated solution.

[0050] Pravastatin sodium Forms A though F may each be obtained byrecrystallization from two-component solvent systems having a proticcomponent and an aprotic component. The term “protic” refers to thepresence of a labile proton like a hydroxyl proton or carboxylic acidproton. Water is a protic solvent. “Aprotic” means the absence of labileprotons. The term “solvents” is used conventionally to mean chemicalcompounds into which a solute, such as pravastatin sodium, is dissolvedor dispersed.

[0051] The pravastatin sodium polymorphs A-F, obtained byrecrystallization, are highly dependent upon the solvent system fromwhich the form is crystallized. Pravastatin sodium tends to crystallizeas Forms A, B and E from solvent systems having a protic component thatis either ethanol or an ethanol:water mixture. In contrast, pravastatinsodium tends to crystallize as forms C, D and F from solvent systemsthat have a protic component that is water alone. We have been able toobtain each of the different forms described above by crystallizingpravastatin sodium from a solvent mixture consisting of a protic solventand an aprotic solvent. The aprotic solvent is selected from ethylacetate, acetonitrile, acetone and acetonitrile:acetone mixtures.

[0052] Temperature is another important parameter for, among otherreasons, its effect on the economics of producing a particular form. Itis highly desirable to be able to conduct a crystallization ofpravastatin sodium at temperatures of −10° C. or above. −10° C. isapproximately the lower limit of temperatures that are obtainable bycooling with cold brine. To obtain lower temperatures, a specializedcooling apparatus, or equivalently, a cooled material like dry ice orliquid nitrogen that has been made cold with a special cooling apparatusmust be used. Consequently, the attainment of lower temperaturesincreases the cost of production. The increased cost may, in fact, beenough to discourage the use of pharmaceuticals in certain crystallineforms with an attendant sacrifice in solubility properties and otherdesirable properties of the crystalline forms. Accordingly, we havedeveloped procedures for crystallizing pravastatin sodium in each of theforms of the present invention that may be conducted at acrystallization temperature of about −10° C. or above. The choice to usea lower temperature is within the province of one skilled in the artinformed by this disclosure.

[0053] In order to obtain each of the pravastatin sodium Forms A throughF in high yield with only moderate cooling, solvent systems that aremoderately to highly concentrated (i.e. typically greater than 0.05 M)in pravastatin sodium have been developed. According to these preferredsolvent systems, the pravastatin sodium is preferably first dissolved inthe protic component of the solvent system. Then, the protic componentis preferably diluted with the aprotic component in order to decreasethe solubility of the pravastatin sodium. The concentration of thepravastatin sodium in the protic component before dilution is notcritical. However, after dilution, the concentration of pravastatinsodium is preferably in the range of 0.05 to 0.5 M. Dilution may beconducted either before, during or after cooling the solution to thecrystallization temperature.

[0054] The aprotic solvent may be a nonpolar solvent, such as hexane,petroleum ether, carbon tetrachloride and the like. The aprotic solventmay also be a polar aprotic solvent. In particular, acetonitrile,acetone, ethyl acetate and acetonitrile:acetone mixtures comprise aspectrum of aprotic components from which each of the novel pravastatinsodium forms may be obtained. Aprotic solvents are preferably used from4 to 20 fold excess on a volume-to-volume basis over the proticcomponent.

[0055] The use of ethanol alone as the protic component of the solventsystem favors the crystallization of pravastatin sodium Form B, providedthe solvent system has been adjusted to a pH of about 8.2 to about 8.7,preferably about 8.5. Equal-volume mixtures of ethanol and water, on theother hand, tend to favor crystallization of Form A. Comparison ofExamples 1 and 2 with Example 3 demonstrates this solvent effect withspecific illustrative embodiments.

[0056] While, generally speaking, the form of pravastatin sodiumobtained by recrystallization is not especially sensitive to the choiceof aprotic solvent among these exemplary aprotic solvents, it will benoted that the use of ethyl acetate in a 20:1 excess over a 1:4H₂O:ethanol protic component promotes crystallization of pravastatinsodium in Form E (See Example 8). This result is to be compared tocrystallization from ethanol and ethanol:water mixtures in Forms A and Bwhich is promoted by an acetonitrile aprotic component (See Examples1-3). In addition, when the acetonitrile is used in an amount that isaround the lower range of the proportion of aprotic component in thesolvent system, i.e. about 4 to about 7 fold excess over the proticcomponent, pravastatin sodium Form B is favored. On the other hand, whenacetonitrile is used in an intermediate amount, i.e. about 13 to about17 fold excess, Form A is favored.

[0057] As noted above, a solvent system having a protic component ofwater alone favors the section crystallization of pravastatin sodium asForms C, D or amorphous Form F. Formation of amorphous Form F ispromoted by adjustment of the pH of the solvent system from about pH 8.7to about pH 10.3, preferably about pH 9 to about pH 10. The pH may beadjusted by contacting with a weak cationic exchange resin such asAmberlite® IRC-50 (See Examples 9 and 10). If the pH is not adjusted,Form F typically is not obtained in pure form. Forms C and D may beobtained from a solvent system wherein water is the only proticcomponent and wherein the pH of the solution is not adjusted for thepurpose of obtaining Form F.

[0058] None of the aforementioned parameters operates independently. So,in the examples concluding this description and preceding the claims,which disclose the best mode for obtaining each of the forms, it will beseen that variations in several parameters at once combine to produce anoptimal yield and purity of the desired form. In particular, the choiceof solvent system, concentration and temperature profile are notindependent. The use of acetonitrile, acetone and acetonitrile:acetonemixtures as the aprotic component, rather than ethyl acetate, allows fora greater concentration of pravastatin sodium in solution at ambienttemperature without premature crystallization. Thus, without heating ofthe solution of pravastatin sodium in the protic component prior todilution, the solution may be diluted with acetone and/or acetonitrileto a range of 0.1 to 0.2 M without premature crystallization (See, e.g.Examples 7, 9-11). When ethyl acetate is used as the aprotic component,the solution of pravastatin sodium in the protic component is preferablyheated to about 40° C. or above, more preferably about 60° C. beforeaddition of the ethyl acetate. Preferably, with heating, ethyl acetateis added to dilute the solution to less than 0.1 M.

[0059] The rate of cooling from ambient or elevated temperature,whichever the case may be, should not be excessively rapid in order torealize maximum selectivity of the other conditions that have beenchosen in order to obtain the desired form. Rapid cooling, typically,will tend to reduce selectivity and result in mixtures of two or moreforms rather than an individual pure form. Accordingly, manipulation ofthe recrystallization parameters to obtain mixtures of the novel formsof pravastatin having desirable characteristics is considered to bewithin the scope of the invention. Typically, in order to obtain any oneof the forms in high purity the rate of cooling may be about from 2° C.h⁻¹ to 35° C. h⁻¹, but the rate of cooling is preferably between about2° C. h⁻¹ to 5.8° C. h⁻¹.

[0060] Once crystallization is complete, the crystals are then isolatedby filtration, decantation of the solvent, removal of the solvent orother such method, preferably filtration. The crystals optionally maythen be washed and dried according to methods known to the art.

[0061] Pravastatin sodium Form G may be prepared by storing pravastatinsodium Form F for 2 weeks at a relative humidity of about 40 to about80%.

[0062] Pravastatin sodium Forms A, H, H1, I, J, K may each be obtainedby conversion from Form D or F. The conversion process consists oftreating pravastatin sodium Form D or F with an alcohol. In oneembodiment the alcohol treatment consists of exposing the firstpolymorph to the vapors of a solvent for a time period. The period oftime may be overnight or may last for three weeks. In an alternativeembodiment the solvent treatment comprises suspended Form D or F in asolvent for a period of time.

[0063] The treatment is performed at room temperature. The temperaturemay be between about 15° C. and 35° C. Optimally, the temperature isabout 25° C.

[0064] The polymorphic form of pravastatin sodium obtained is dependenton the treatment solvent. For example, treating Form D or F with ethanolvapors produces Form A. Treating form D or F with methanol vaporsproduces Form H. The relationship between the treatment solvent and thepolymorphic form of pravastatin sodium produced is summarized in TableI, and illustrated in Example 15, 16, 17, 18, 19, and 20. TABLE IStarting Resulting Incubation Polymorph Polymorph Solvent Time ExposureD or F A Ethanol 3 weeks Vapors D or F H Methanol 3 weeks Vapors D or FH1 Methanol Overnight Suspension D or F I Isopropyl 3 weeks VaporsAlcohol D or F J Butanol 3 weeks Vapors D or F K Ethanol, OvernightSuspension Isopropyl Alcohol and Butanol

[0065] Most of these forms have a jelly appearance. By drying thesesamples at 60° C., vacuum overnight, the powdered Form D is obtained.

[0066] Treatment of Hypercholesteremia with Pravastatin SodiumPolymorphs

[0067] More pravastatin sodium Forms A, B, C, D, E, F, G, H, H1, I, J, Kand L are useful for hypercholesteremia therapy and for this purposethey are administered to a mammalian patient in a dosage form. Dosageforms may be adapted for administration to the patient by oral, buccal,parenteral, ophthalmic, rectal and transdermal routes. Oral dosage formsinclude tablets, pills, capsules, troches, sachets, suspensions,powders, lozenges, elixirs and the like. The pravastatin sodium formsalso may be administered as suppositories, ophthalmic ointments andsuspensions, and parenteral suspensions, which are administered by otherroutes. The most preferred route of administration of the pravastatinsodium forms of the present invention is oral.

[0068] While the description is not intended to be limiting, theinvention does not pertain to true solutions of any of the novelpravastatin sodium forms in which the properties of the solid forms ofpravastatin sodium are lost. However, the use of the novel forms toprepare such solutions (e.g. so as to deliver, in addition topravastatin sodium, a solvate to said solution in a certain ratio with asolvate) is considered to be within the contemplated invention.

[0069] The dosage forms may contain one or more of the novel forms ofpravastatin sodium or, alternatively, may contain one or more of thenovel forms of pravastatin sodium in a composition. Whether administeredin pure form or in a composition, the pravastatin sodium form(s) may bein the form of a powder, granules, aggregates or any other solid form.The compositions of the present invention include compositions fortableting. Tableting compositions may have few or many componentsdepending upon the tableting method used, the release rate desired andother factors. For example, compositions of the present invention maycontain diluents such as cellulose-derived materials like powderedcellulose, microcrystalline cellulose, microfine cellulose, methylcellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose saltsand other substituted and unsubstituted celluloses; starch;pregelatinized starch; inorganic diluents like calcium carbonate andcalcium diphosphate and other diluents known to the pharmaceuticalindustry. Yet other suitable diluents include waxes, sugars and sugaralcohols like mannitol and sorbitol, acrylate polymers and copolymers,as well as pectin, dextrin and gelatin.

[0070] Further excipients that are within the contemplation of thepresent invention include binders, such as acacia gum, pregelatinizedstarch, sodium alginate, glucose and other binders used in wet and drygranulation and direct compression tableting processes. Excipients thatmay also be present in a solid composition of the novel forms ofpravastatin sodium further include disintegrants like sodium starchglycolate, crospovidone, low-substituted hydroxypropyl cellulose andothers. Additional excipients include tableting lubricants likemagnesium and calcium stearate and sodium stearyl fumarate; flavorings;sweeteners; preservatives; pharmaceutically acceptable dyes and glidantssuch as silicon dioxide.

[0071] Capsule dosages, of course, will contain the solid compositionwithin a capsule which may be made of gelatin or other encapsulatingmaterial. Tablets and powders may be coated. Tablets and powders may becoated with an enteric coating. The enteric-coated powder forms may havecoatings comprising phthalic acid cellulose acetate, hydroxypropylmethylcellulose phthalate, polyvinyl alcohol phthalate,carboxymethylethylcellulose, a copolymer of styrene and maleic acid, acopolymer of methacrylic acid and methyl methacrylate, and likematerials, and if desired, they may be employed with suitableplasticizers and/or extending agents. A coated tablet may have a coatingon the surface of the tablet or may be a tablet comprising a powder orgranules with an enteric-coating.

[0072] In human subjects with normal hepatic function and moderate bodyweight, a reduction in serum cholesterol levels is typically observedwith daily dosages of 10 mg or more of pravastatin sodium. A daily oralregimen is the most commonly prescribed method of administration.Preferred oral dosages of the present invention contain from about 10 mgto about 40 mg of pravastatin sodium Forms A, B, C, D, E, F, G, H, H1,I, J, K, and L or their mixtures.

[0073] Having thus described the present invention with reference tocertain preferred embodiments, the following examples are provided tofurther illustrate methods by which novel Forms A, B, C, D, E, F, G, H,H1, I, J, K, and L of pravastatin sodium may be obtained. One skilled inthe art will recognize variations and substitutions in the methods asdescribed and exemplified which do not depart from the spirit and scopeof the invention.

EXAMPLES

[0074] “Ethanol” refers to absolute ethanol. Acetonitrile, acetone andethyl acetate were regular grade.

Example 1 Preparation of Pravastatin Sodium Form A

[0075] Pravastatin sodium (5 g) was dissolved in a 1:1 mixture ofethanol:water (5 ml).

[0076] The pH was raised to 8.5 by addition of 2M sodium hydroxide inwater (1.2 ml) and the solution was heated to 50° C. Acetonitrile (90ml) was added to the mixture and then the mixture was stirred atelevated temperature for one hour. The mixture was allowed to cool to20-25° C. (“ambient temperature”), was held at ambient temperature fortwo hours and then cooled to 5° C. and maintained at 5° C. for 12 hours,whereupon pravastatin sodium crystallized. The crystals were thenisolated by filtration and washed with acetonitrile (2×10 ml) and driedunder vacuum at 50° C. X-ray diffraction analysis revealed the presenceof Form A. Pravastatin Form A was obtained in 92% yield.

Example 2 Preparation of Pravastatin Statin Form A

[0077] Pravastatin sodium (5 g.) was dissolved in a 2.85:1 mixture ofethanol:water (10.8 ml). The pH was raised to 8.5 by addition of 2Msodium hydroxide in water (1.2 ml). Acetonitrile (200 ml) was thenslowly added to the mixture at ambient temperature over a two hourperiod. The mixture was stirred at ambient temperature for another twohours and then cooled to 5° C. and maintained at 5° C. for 12 hours,whereupon pravastatin sodium crystallized. The crystals were thenisolated by filtration and washed with acetonitrile (2×10 ml) and driedunder vacuum at 50° C. X-ray diffraction analysis revealed the presenceof Form A. Pravastatin sodium Form A was obtained in 96% yield.

Example 3 Preparation of Pravastatin Sodium Form B

[0078] Pravastatin sodium (5 g) was dissolved in ethanol (35.5 ml). ThepH was raised to 8.5 by addition of 2M sodium hydroxide in water (1.5ml). The basic solution was heated to 60° C. and then diluted withacetonitrile (213 ml). The solution was maintained at elevatedtemperature for one hour and then was allowed to cool to ambienttemperature and was maintained at ambient temperature for two hours. Thesolution was then cooled to 5° C. and maintained at that temperature for12 hours, whereupon pravastatin sodium crystallized. The crystals wereisolated by filtration and rinsed, first with ethyl acetate (2×45 ml)and second with n-hexane (2×45 ml). The rinse solvents had beenprecooled to 5° C. After rinsing, the crystals were dried under vacuumat 50° C. X-ray diffraction analysis revealed the presence of Form B.Pravastatin sodium Form B was obtained in 87% yield.

Example 4 Preparation of Pravastatin Sodium Form C

[0079] Pravastatin sodium (10 g) was dissolved in deionized water (26ml) and diluted with a 2:3 mixture of acetonitrile:acetone (130 ml). Theresulting solution was then warmed to 40° C. and maintained at thattemperature for one half hour while acetonitrile (160 ml) was slowlyadded. The solution was then cooled to 5° C. While cooling, pravastatinsodium began to crystallize at 19.5° C. The mixture was maintained at 5°C. for five hours, after which time the crystals were isolated byfiltration, washed with acetone that had been pre-cooled to 5° C., anddried under vacuum at 50° C. X-ray diffraction analysis revealed thepresence of Form C. Pravastatin sodium Form C was obtained in 76% yield.

Example 5 Preparation of Pravatatin Sodium Form D

[0080] Pravastatin sodium (600 g) was dissolved in 0.73 M sodiumhydroxide in water (600 ml). The resulting solution was diluted withacetonitrile (1.2 L) and then decolorized by stirring over charcoal (30g) for 30 min. The charcoal was removed by filtration and rinsed with2:1 acetone:water (1.8 L). The pravastatin sodium solution and rinsatewere combined and diluted with acetonitrile (17 L). The dilute solutionwas maintained at ambient temperature (20-25° C.) for one hour and thencooled to 5° C. and stirred at that temperature for 4 hours, whereuponpravastatin sodium crystallized. The crystals were filtered and slurriedwith ethyl acetate (6 L) at 5° C. to remove residual acetonitrile. Thecrystals were then washed with ethyl acetate that had been pre-cooled to−5° C. and dried under vacuum at 50° C. X-ray diffraction analysisrevealed the presence of Form D. Pravastatin sodium Form D was obtainedin 97% yield.

Example 6 Preparation of Pravastatin Sodium Form D

[0081] Pravastatin sodium (7 g) was dissolved in deionized water (13 ml)and diluted with acetone (14.3 ml). The resulting solution was stirredover charcoal (0.07 g.) to decolorize. The charcoal was removed byfiltration and rinsed with a 10:1 mixture of acetone:water (15.7 ml).The combined pravastatin sodium solution and rinsate was then dilutedwith acetone (42.8 ml) and cooled to −10° C. At the reduced temperature,more acetone (143 ml) was slowly added over one half hour. The solutionwas then maintained at −10° C. for three hours during which timepravastatin sodium crystallized. The crystals were then isolated byfiltration, washed with 1% water in acetone that had been pre-cooled to−10° C. (28 ml) and then again with anhydrous acetone (28 ml). Thecrystals were then dried under vacuum at 50° C. X-ray diffractionanalysis revealed the presence of Form D. The conversion of amorphouspravastatin sodium to pravastatin sodium Form D occurred in 85% yield.Before drying the crystals were Form L, after drying the crystals wereForm D.

Example 7 Preparation of Pravastatin Sodium Form D

[0082] Pravastatin sodium (25 g) was dissolved in deionized water (65ml) and diluted with 1:1.44 acetonitrile:acetone (330 ml). The resultingsolution was cooled to 5° C. While cooling, pravastatin sodium startedto crystallize at 9° C. After crystallization appeared to cease, acetonethat had been precooled to 5° C. (650 ml) was added to the mixture andthe mixture was maintained at 5° C. for another three hours. Thecrystals were isolated by filtration and washed with 1:3:22water:acetone:acetonitrile that had been pre-cooled to 5° C. (25 ml).The crystals were then slurried with ethyl acetate that had beenpre-cooled to 5° C. (50 ml) and dried under vacuum at 50° C. X-raydiffraction analysis revealed the presence of Form D. Pravastatin sodiumForm D was obtained in 70% yield.

Example 8 Preparation of Pravastatin Sodium Form E

[0083] Pravastatin sodium (5 g) was dissolved in 4:1 ethanol:water (12.5ml) and warmed to 60° C. The solution was then diluted with ethylacetate (250 ml) and the dilute solution was maintained at elevatedtemperature for one hour. The solution was then allowed to cool toambient temperature and was maintained at that temperature for twohours. The solution was then cooled to 5° C. and maintained at reducedtemperature for three hours, whereupon pravastatin sodium crystallized.The crystals were isolated by filtration, rinsed with ethyl acetate(2×30 ml) and dried under vacuum at 50° C. X-ray diffraction analysisshowed the presence of Form E. Pravastatin sodium Form E was obtained87% yield.

Example 9 Preparation of Pravastatin Sodium Form F

[0084] Pravastatin sodium (10 g) was dissolved in water (24.5 ml) anddiluted with acetonitrile (26 ml). The resulting solution was stirredover charcoal (0.1 g.) to decolorize. Amberlite® IRC-50 cationic ionexchange resin (^(H+) form) was added to the stirred mixture to raisethe pH to 9.09. The charcoal and ion exchange resin were removed byfiltration and rinsed with a 10:1 mixture of acetonitrile:water (16.5ml). The combined pravastatin sodium solution and rinsate was dilutedwith 2.1:1 acetone:acetonitrile (115 ml), cooled to 5° C. and maintainedat reduced temperature for two hours. pravastatin sodium crystallized.After crystallization appeared to cease, acetonitrile (260 ml) that hadbeen pre-cooled to 5° C. was added and the mixture was maintained atreduced temperature for another three hours. The crystals were isolatedby filtration and washed with 1:3:22 water:acetone:acetonitrile (40 ml)that had been pre-cooled to 5° C. The crystals were then slurried withprecooled ethyl acetate (100 ml) and dried under vacuum at 50° C. X-raydiffraction analysis showed the presence of Form F. Pravastatin sodiumForm F was obtained in 74% yield.

Example 10 Preparation of Pravastatin Sodium Form F

[0085] Pravastatin sodium (10 g) was dissolved in deionized water (24.5ml) and diluted with acetonitrile (26 ml). The resulting solution wasstirred over charcoal (0.1 g.) to decolorize. Then, the pH was raised to9.01 by addition of Amberlite® IRC-50 cationic exchange resin (H⁺ form).The charcoal was removed by filtration and rinsed with a 10:1 mixture ofacetonitrile:water (16.5 ml). The combined pravastatin sodium solutionand rinsate was then diluted with 2.1:1 acetone:acetonitrile (115 ml)and cooled to 5° C. The solution was maintained at reduced temperaturefor three hours, during which time pravastatin sodium crystallized. Thecrystals were isolated by filtration and washed with 1:3:22water:acetone:acetonitrile that had been pre-cooled to 5° C. (40 ml).The crystals were slurried with ethyl acetate that had been pre-cooledto 5° C. and then dried under vacuum at 50° C. X-ray diffractionanalysis showed the presence of Form F. Pravastatin sodium Form F wasobtained in 90% yield.

Example 11 Preparation of Pravastatin Sodium Form F

[0086] Pravastatin sodium (5 g) was dissolved in deionized water (13 ml)and diluted with acetone (65 ml). The resulting solution was cooled to5° C. While cooling, pravastatin sodium Form F began to crystallize at9° C. The mixture was maintained at 5° C. for five hours. Then, acetonethat had been pre-cooled to 5° C. was added to the mixture and themixture was kept at 5° C. for another three hours, after which timecrystallization was judged to be complete. The crystals were thenisolated by filtration, washed with acetone that had been pre-cooled to5° C. (10 ml) and dried under vacuum at 50° C. Pravastatin sodium Form Fwas obtained in 87% yield.

Example 12 Preparation of Mixture of Pravastatin Sodium Forms D and F

[0087] Pravastatin sodium (10 g.) was dissolved in deionized water (24.5ml) and diluted with acetonitrile (26 ml). The resulting solution wasstirred over charcoal (0.1 g.) to decolorize. The charcoal was removedby filtration and rinsed with a 10:1 mixture of acetonitrile:water (16.5ml). The combined pravastatin sodium solution and rinsate was dilutedwith acetonitrile (11 ml) and warmed to 40° C. At the elevatedtemperature, acetone (60 ml) was slowly added over one half hour. Thesolution was then cooled to a temperature of 10° C. over three hours.After the solution had attained a temperature of 12° C., the mixture wasseeded with a crystal of pravastatin sodium Form D. At 11.3° C., thesolution was diluted with acetone (200 ml). After the three hours hadpassed, the mixture of solution and crystals was cooled to 5° C. andmaintained at that temperature for three hours. The crystals were thenremoved by filtration, washed with acetone that had been pre-cooled to5° C. (40 ml) and dried under vacuum at 50° C. The crystals were foundby X-ray diffraction to be a mixture of pravastatin sodium Form D andForm F. The mixture of pravastatin sodium Forms D and F was obtained in77% yield.

Example 13 Preparation of Mixture of Pravastatin Sodium Forms C and D

[0088] Pravastatin sodium (10 g) was dissolved in deionized water (18ml) and diluted with acetone (20 ml). The resulting solution was stirredover charcoal (0.1 g) to decolorize. The charcoal was removed byfiltration and rinsed with a 10:1 mixture of acetonitrile:water (20 ml).The combined pravastatin sodium solution and rinsate was then dilutedwith acetone (60 ml) and warmed to 40° C. The solution was maintained atelevated temperature for half an hour while acetone (190 ml) was slowlyadded. The solution was cooled to 10° C. While being cooled, thesolution was seeded with a crystal of pravastatin sodium Form D at 13°C. The solution was then maintained at 10° C. for three hours. Thenacetone (190 ml) was added and the solution was cooled to 5° C. Another190 ml of acetone was added and the mixture was stirred at 50° C. forthree hours, during which time crystallization was complete. Thecrystals were isolated by filtration, washed with acetone that had beenpre-cooled to 5° C., and dried under vacuum at 50° C. The crystals wereidentified by X-ray diffraction as a mixture of pravastatin sodium FormsC and D. The mixture of pravastatin sodium Forms C and D was obtained in89% yield.

Example 14 Preparation of Pravastatin Sodium Form F

[0089] Pravastatin sodium (10 g) was dissolved in deionized water (20ml). The pH of the aqueous solution was adjusted to 7.1 by addition ofAmberlite® IRC-50 cationic ion exchange resin (H⁺ form). The solutionwas then diluted with acetone (120 ml) and then heated to 40° C. Another130 ml of acetone was slowly added to the mixture over a period of 30min. The solution was then cooled to 5° C. over 3 hours. When themixture reached a temperature of 25° C., it was seeded with crystals ofForm F. The mixture was maintained at 5° C. for 20 h, over which timepravastatin sodium crystallized from the mixture. The crystals wereisolated by filtration and washed with acetone (40 ml). The crystalswere then dried under vacuum at 60° C. X-ray diffraction analysis showedthe presence of Form F. Pravastatin sodium Form F was obtained in 84%yield.

Example 15 Preparation of Pravastatin Sodium Form G

[0090] Pravastatin Form G is obtained when pravastatin Form F is storedfor two weeks at relative humidity of between 40-80%. The resultingsolid was analyzed by X-ray diffraction without further treatment.

Example 16 Preparation of Pravastatin Sodium Form H

[0091] Pravastatin sodium Form H was prepared by treating Form D or Fwith ethanol vapors for three weeks at room temperature. The procedurewas as follows. A 100-200 g sample of pravastatin sodium Form D or F waskept in a 10 ml open glass bottle. The open bottle was introduced into alarger bottle containing ethanol. The larger bottle was sealed in orderto create a saturated atmosphere. The resulting solid was analyzed byX-Ray diffraction without further treatment. Form H could also beconverted to Form D by drying under vacuum overnight.

Example 17 Preparation of Pravastatin Sodium Form H1

[0092] Pravastatin sodium Form H1 was prepared by suspending about 0.5to 1.4 g of Form D in about 0.6 ml methanol overnight at roomtemperature, in a sealed 1.10 ml bottle with a sealed cap and a magneticstirrer The resulting solid was analyzed by X-ray diffraction analysiswithout further treatment.

Example 18 Preparation of Pravastatin Sodium Form I

[0093] Pravastatin sodium Form I was prepared by treating Form D or Fwith isopropyl vapors for three weeks at room temperature. The procedurewas as follows. A 100-200 g sample of pravastatin sodium Form D or F waskept in a 10 ml open glass bottle. The open bottle was introduced into alarger bottle containing few ml of isopropyl alcohol. The larger bottlewas sealed in order to create a saturated atmosphere. The resultingsolid was analyzed by X-Ray diffraction analysis without furthertreatment. Form I could also be transformed to Form D by drying undervacuum overnight.

Example 19 Preparation of Pravastatin Sodium Form J

[0094] Pravastatin sodium Form J was prepared by treating Form D or Fwith butanol vapors for three weeks at room temperature. The procedurewas as follows. A 100-200 g sample of pravastatin sodium Form D or F waskept in a 10 ml open glass bottle. The open bottle was introduced into alarger bottle containing few ml of butanol. The larger bottle was sealedin order to create a saturated atmosphere. The resulting solid wasanalyzed by X-Ray diffraction analysis without further treatment. Form Jcould also be transformed to Form D by drying under vacuum overnight.

Example 20 Preparation of Pravastatin Sodium Form K

[0095] Pravastatin sodium Form K was obtained by suspending 0.8 gpravastatin in about 2 ml ethanol and stirring overnight at RT. Theresulting solid was analyzed by X-Ray diffraction analysis withoutfurther treatment.

Example 21 Preparation of Pravastatin Sodium Form D

[0096] Pravastatin sodium(about 100 mg) of any polymorph beside Forms Bor D was kept in an oven at 120° C. for 2 hours. The powder was thenanalyzed by X-ray diffraction and found to be Form D.

Example 22 Preparation of Pravastatin Sodium Form C

[0097] Pravastatin sodium was exposed at 100% relative humidity for oneweek. The power was then analyzed by X-ray diffraction without furthertreatment and was found to be Form C.

Example 23 Preparation of Pravastatin Sodium Form L and Form D

[0098] A solution was prepared, containing 80 kg pravastatin sodium and144 kg water. The pH of the solution was set to 7.2, by IRC-50 weaklyacidic cation exchange resin. Acetone (320 L) was added to the solutionand it was treated with 0.8 kg charcol to decolorize. The charcoal wasfiltered with a solution of acetone:water, 10:1 (176 L). The solutionwas warmed to 40° C. Acetone (176 L) was added to the solution. Themixture is cooled at a rate of 2° C./h⁻¹ rate. The solution is seeded at32° C. by 0.1% (0.08 kg) pravastatin sodium (Form D). The mixture wascooled to 2° C. and stirred for 2-4 hour.

[0099] Pravastatin crystals were filtered and washed with 160 L acetonecontaining 2% water and cooled to between 2-5° C. Then the wet cake waswashed once more with 160 L of pure acetone. The product was dried undervacuum by gradual heating to 60° C. The crystals were identified byX-ray diffraction as Form L. The water content was 16.8% and the acetonecontent was 0%. After prolonged drying the water content was reduced to10.7%. A mixture of Form L and D was identified. Further drying reducedthe water content to 2.5% water content and the pravastatin sodium wastransformed to pure Form D.

We claim:
 1. Crystalline pravastatin sodium and hydrates thereof havingan X-ray powder diffraction pattern comprising characteristic peaks at3.9, 4.5, 6.2, 7.2, and 20.0±0.2 degrees measured at reflection angle2θ.
 2. Crystalline pravastatin sodium of claim 1 wherein the X-raypowder diffraction pattern further comprises peaks at 8.6, 9.2, 10.0,11.6, 12.0, and 17.0±0.2 degrees measured at reflection angle 2θ. 3.Crystalline pravastatin sodium and hydrates thereof having an infraredspectrum obtained in Nujol Moll comprising absorption bands at 826, 842,864, 1156, 1184 and 1576±4 cm⁻¹.
 4. Crystalline pravastatin sodium ofclaim 3 wherein the infrared spectrum further comprises absorption bandsat 686, 842, 864, 917, 939, 965, 1013, 1040, 1092, 1111, 1156, 1265,1310, 1330, and 1726±2 cm⁻¹.
 5. A pharmaceutical composition comprisingthe crystalline polymorph of claim 1 and a pharmaceutically acceptablecarrier.
 6. A method for treating a patient suffering fromatherosclerosis or hypercholesteremia by administering a therapeuticallyeffective amount of the pharmaceutical composition of claim 5 . 7.Pravastatin sodium Form A.
 8. Crystalline pravastatin sodium andhydrates thereof having an X-ray powder diffraction pattern comprisingcharacteristic peaks at 3.6, 6.1 and 6.6 ±0.2 degrees measured atreflection angle 2θ.
 9. Crystalline pravastatin sodium of claim 8wherein the X-ray powder diffraction pattern further comprises peaks at9.0, 9.6, 10.1, 16.4, 16.8 and 18.6±0.2 degrees measured at reflectionangle 2θ.
 10. Crystalline pravastatin sodium and hydrates thereof havingan infrared spectrum obtained in Nujol Moll comprising absorption bandsat 1149, 1161, 1563 and 1606±2 cm⁻¹.
 11. Crystalline pravastatin sodiumof claim 3 wherein the infrared spectrum further comprises absorptionbands at 614, 692, 739, 824, 842, 854, 868, 901, 914, 936, 965, 1011,1028, 1039, 1072, 1091, 1111, 1129, 1185, 1232, 1245, 1318, 1711 and1730±2 cm⁻¹.
 12. A pharmaceutical composition comprising the crystallinepolymorph of claim 8 and a pharmaceutically acceptable carrier.
 13. Amethod for treating a patient suffering from atherosclerosis orhypercholesteremia by administering a therapeutically effective amountof the pharmaceutical composition of claim 12 .
 14. Pravastatin sodiumForm B.
 15. Crystalline pravastatin sodium and hydrates thereof havingan X-ray powder diffraction pattern comprising characteristic peaks at13.0, 15.5, 16.0 and 21.0±0.2 degrees measured at reflection angle 2θ.16. Crystalline pravastatin sodium of claim 15 wherein the X-ray powderdiffraction pattern further comprises peaks at 4.8, 7.6, 8.7, 10.0,11.8, 12.4, 17.4, 17.9, 18.4, 19.7, 21.8 and 22.8±0.2 degrees measuredat reflection angle 2θ.
 17. Crystalline pravastatin sodium and hydratesthereof having an infrared spectrum obtained in Nujol Moll comprisingabsorption bands at 829, 851, 1078, 1090, 1567, and 1728 ±2 cm⁻¹. 18.Crystalline pravastatin sodium of claim 17 wherein the infrared spectrumfurther comprises absorption bands at 742, 870, 926, 940, 964, 1013,1038, 1146, 1166, 1174, 1194, 1257, 1268, 1313 and 1328±2 cm⁻¹.
 19. Apharmaceutical composition comprising the crystalline pravastatin sodiumof claim 15 and a pharmaceutically acceptable carrier.
 20. A method fortreating a patient suffering from atherosclerosis or hypercholesteremiaby administering a therapeutically effective amount of thepharmaceutical composition of claim 19 .
 21. Pravastatin sodium Form C.22. Crystalline pravastatin sodium and hydrates thereof having an X-raypowder diffraction pattern comprising characteristic peaks at 6.3 and9.8±0.2 degrees measured at reflection angle 2θ.
 23. Crystallinepravastatin sodium of claim 22 wherein the X-ray powder diffractionpattern further comprises peaks at 3.6 and 17.1±0.2 degrees measured atreflection angle 2θ.
 24. Crystalline pravastatin sodium and hydratesthereof having an infrared spectrum obtained in Nujol Moll comprisingabsorption bands at 824, 842, 854, 1157, 1186, 1566, and 1606±2 cm⁻¹.25. Crystalline pravastatin sodium of claim 24 wherein the infraredspectrum further comprises absorption bands at 854, 914, 939, 965, 1013,1041, 1079, 1091, 1266, and 1728±2 cm⁻¹.
 26. A pharmaceuticalcomposition comprising the crystalline pravastatin sodium of claim 22and a pharmaceutically acceptable carrier.
 27. A method for treating apatient suffering from atherosclerosis or hypercholesteremia byadministering a therapeutically effective amount of the pharmaceuticalcomposition of claim 26 .
 28. Pravastatin sodium Form D.
 29. Crystallinepravastatin sodium and hydrates thereof having an X-ray powderdiffraction pattern comprising characteristic peaks at 4.6, 10.3, 12.1,and 16.6±0.2 degrees measured at reflection angle 2θ.
 30. Crystallinepravastatin sodium of claim 29 wherein the X-ray powder diffractionpattern further comprises peaks at 9.2, 11.2, 18.3 and 20.6±0.2 degreesmeasured at reflection angle 2θ.
 31. Crystalline pravastatin sodium andhydrates thereof having an infrared spectrum obtained in Nujol Mollcomprising absorption bands at 1016, 1043, 1158, 1179, 1573 and 1727±2cm⁻¹.
 32. Crystalline pravastatin sodium of claim 31 wherein theinfrared spectrum further comprises absorption bands at 781, 829, 853,939, 964, 1078, 1266, 1300, 1329 and 1401±2 cm⁻¹.
 33. A pharmaceuticalcomposition comprising the crystalline pravastatin sodium of claim 29and a pharmaceutically acceptable carrier.
 34. A method for treating apatient suffering from atherosclerosis or hypercholesteremia byadministering a therapeutically effective amount of the pharmaceuticalcomposition of claim 33 .
 35. Pravastatin sodium Form E.
 36. Amorphouspravastatin sodium and hydrates thereof having an X-ray powderdiffraction pattern comprising a characteristic peak at 4.6±0.2 degreesmeasured at reflection angle 2θ.
 37. Amorphous pravastatin sodium andhydrates thereof having an infrared spectrum obtained in Nujol Mollcomprising absorption bands at 1157, 1181, 1576, and 1727±2 cm⁻¹. 38.Amorphous pravastatin sodium of claim 37 wherein the infrared spectrumfurther comprises absorption bands at 781, 829, 853, 939, 964, 1016,1043, 1079, 1265, 1300, 1330 and 1400±2 cm⁻¹.
 39. A pharmaceuticalcomposition comprising the amorphous pravastatin sodium of claim 36 anda pharmaceutically acceptable carrier.
 40. A pharmaceutical compositioncomprising amorphous pravastatin sodium and a pharmaceuticallyacceptable carrier.
 41. A method for treating a patient suffering fromatherosclerosis or hypercholesteremia by administering a therapeuticallyeffective amount of the pharmaceutical composition of claim 39 . 42.Pravastatin sodium Form F.
 43. Amorphous pravastatin.
 44. Crystallinepravastatin sodium and hydrates thereof having an X-ray powderdiffraction pattern comprising characteristic peak at 4.5, 9.2, 10.0,12.2, 16.0, 16.5, 17.6, 18.6, 19.5, 20.5 and 22.8±0.2 degrees measuredat reflection angle 2θ.
 45. A pharmaceutical composition comprising thecrystalline pravastatin sodium of claim 44 and a pharmaceuticallyacceptable carrier.
 46. A method for treating a patient suffering fromatherosclerosis or hypercholesteremia by administering a therapeuticallyeffective amount of the pharmaceutical composition of claim 45 . 47.Pravastatin sodium Form G.
 48. Crystalline pravastatin sodium andhydrates thereof having an X-ray powder diffraction pattern comprisingcharacteristic peaks at 3.5, 5.9, 9.0, 10.1 and 17.0±0.2 degreesmeasured at reflection angle 2θ.
 49. Crystalline pravastatin sodium ofclaim 48 wherein the X-ray powder diffraction pattern further comprisespeaks at 11.7, 12.1, 14.7, 19.0, 19.9, 20.6, 21.8 and 22.9±0.2 degreesmeasured at reflection angle 2θ.
 50. A pharmaceutical compositioncomprising the crystalline pravastatin sodium of claim 48 and apharmaceutically acceptable carrier.
 51. A method for treating a patientsuffering from atherosclerosis or hypercholesteremia by administering atherapeutically effective amount of the pharmaceutical composition ofclaim 50 .
 52. Pravastatin sodium Form H.
 53. Crystalline pravastatinsodium and hydrates thereof having an X-ray powder diffraction patterncomprising characteristic peaks at 3.5, 5.9, 8.9, 10.1, 17.6, 18.8 and20.8±0.2 degrees measured at reflection angle 2θ.
 54. Crystallinepravastatin sodium of claim 53 wherein the X-ray powder diffractionpattern further comprises peaks at 6.8, 11.7, 12.3, 13.3, 14.8, 20.0 and22.9±0.2 degrees measured at reflection angle 2θ.
 55. A pharmaceuticalcomposition comprising the crystalline pravastatin sodium of claim 52and a pharmaceutically acceptable carrier.
 56. A method for treating apatient suffering from atherosclerosis or hypercholesteremia byadministering a therapeutically effective amount of the pharmaceuticalcomposition of claim 53 .
 57. Pravastatin sodium Form H1. 58.Crystalline pravastatin sodium and hydrates thereof having an X-raypowder diffraction pattern comprising characteristic peaks at 4.4, 5.2,5.8, 6.5, 13.2, and 14.0±0.2 degrees measured at reflection angle 2θ.59. Crystalline pravastatin sodium of claim 58 wherein the X-ray powderdiffraction pattern further comprises peaks at 7.5, 8.3, 9.8, 10.2,11.2, 16.5, 17.5, 18.3, 18.6, 19.5, 20.5, 21.5 and 23.0±0.2 degreesmeasured at reflection angle 2θ.
 60. A pharmaceutical compositioncomprising the crystalline pravastatin sodium of claim 56 and apharmaceutically acceptable carrier.
 61. A method for treating a patientsuffering from atherosclerosis or hypercholesteremia by administering atherapeutically effective amount of the pharmaceutical composition ofclaim 58 .
 62. Pravastatin sodium Form I.
 63. Crystalline pravastatinsodium and hydrates thereof having an X-ray powder diffraction patterncomprising characteristic peaks at 3.8, 6.0, and 16.3±0.2 degreesmeasured at reflection angle 2θ.
 64. Crystalline pravastatin sodium ofclaim 63 wherein the X-ray powder diffraction pattern further comprisespeaks at 3.3, 6.8, 7.5, 8.8, 9.3, 10.2, 11.2, 11.7, 13.5, 13.9, 14.5,15.6, 17.7, 18.1, 18.7, 19.5, 20.0, 20.3, 21.7, 22.3, 24.2, and 26.1±0.2degrees measured at reflection angle 2θ.
 65. A pharmaceuticalcomposition comprising the crystalline pravastatin sodium of claim 62and a pharmaceutically acceptable carrier.
 66. A method for treating apatient suffering from atherosclerosis or hypercholesteremia byadministering a therapeutically effective amount of the pharmaceuticalcomposition of claim 63 .
 67. Pravastatin sodium Form J.
 68. Crystallinepravastatin sodium and hydrates thereof having an X-ray powderdiffraction pattern comprising a broad peak between 15 and 25±0.2degrees measured at reflection angle 2θ.
 69. A pharmaceuticalcomposition comprising the crystalline pravastatin sodium of claim 68and a pharmaceutically acceptable carrier.
 70. A method for treating apatient suffering from atherosclerosis or hypercholesteremia byadministering a therapeutically effective amount of the pharmaceuticalcomposition of claim 68 .
 71. Pravastatin sodium Form K.
 72. Crystallinepravastatin sodium and hydrates thereof having an X-ray powderdiffraction pattern comprising characteristic peaks at 16.6, 17.6, and18.5±0.2 degrees measured at reflection angle 2θ.
 73. Crystallinepravastatin sodium of claim 72 wherein the X-ray powder diffractionpattern further comprises peaks at 4.5, 5.0, 9.0, 10.1, 12.3, 13.4,15.0, 19.5, 20.2, and 22.7±0.2 degrees measured at reflection angle 2θ.74. A pharmaceutical composition comprising the crystalline pravastatinsodium of claim 72 and a pharmaceutically acceptable carrier.
 75. Amethod for treating a patient suffering from atherosclerosis orhypercholesteremia by administering a therapeutically effective amountof the pharmaceutical composition of claim 72 .
 76. Pravastatin sodiumForm L.
 77. A process for preparing pravastatin sodium Form A comprisingthe steps of: (a) dissolving any solid form of pravastatin sodium in aprotic solvent to form a solution; (b) diluting the solution ofpravastatin sodium with an aprotic solvent; and (c) crystallizing thepravastatin sodium Form A from the solution of pravastatin sodium. 78.The process of claim 77 wherein the protic solvent is a mixture ofethanol and water.
 79. The process of claim 77 wherein the aproticsolvent is a polar aprotic solvent.
 80. The process of claim 78 whereinthe polar aprotic solvent is acetonitrile.
 81. The process of claim 77wherein the aprotic solvent is a non-polar solvent.
 82. The process ofclaim 81 wherein the non-polar solvent is selected from the groupconsisting hexane, petroleum, ether and carbon tetrachloride.
 83. Theprocess of claim 77 wherein crystallizing pravastatin sodium isperformed at a temperature of between about −10° C. and 10° C.
 84. Theprocess of claim 83 wherein the temperature is about −10° C.
 85. Theprocess of claim 83 wherein the temperature is about 10° C.
 86. Theprocess of claim 83 wherein the temperature is about 5° C.
 87. Theprocess of claim 77 further comprising cooling the solution ofpravastatin sodium.
 88. The process of claim 77 further comprisingcooling the solution of pravastatin sodium at a rate of about 5.8° C.per hour to about 35° C. per hour.
 89. The process of claim 77 furthercomprising cooling the solution of pravastatin sodium at a rate of about2° C. per hour.
 90. The process of claim 77 wherein pravastatin sodiumis at a concentration of about 0.05 to 0.5 M after dilution with theprotic solvent.
 91. The process of claim 77 further comprising heatingthe solution of pravastatin sodium to a temperature above 40° C. priorto the addition of the aprotic solvent.
 92. The process of claim 91wherein the temperature is about 60° C.
 93. A process for preparingpravastatin sodium Form B comprising the steps of: (a) dissolving anysolid form of pravastatin sodium in a protic solvent to form a solution;(b) diluting the solution of pravastatin sodium with an aprotic solvent;and (c) crystallizing the pravastatin sodium Form B from the solution ofpravastatin sodium.
 94. The process of claim 93 wherein the proticsolvent is ethanol.
 95. The process of claim 93 wherein the aproticsolvent is a polar aprotic solvent.
 96. The process of claim 95 whereinthe polar aprotic solvent is acetonitrile.
 97. The process of claim 95wherein the polar aprotic solvent is a mixture of solvents selected fromthe group consisting of acetonitrile, acetone, and ethyl acetate. 98.The process of claim 93 wherein the aprotic solvent is a non-polarsolvent.
 99. The process of claim 98 wherein the non-polar solvent isselected from the group consisting hexane, petroleum, ether and carbontetrachloride.
 100. The process of claim 93 wherein crystallizingpravastatin sodium is performed at a temperature of between about −10°C. and 10° C.
 101. The process of claim 100 wherein the temperature isabout −10° C.
 102. The process of claim 100 wherein the temperature isabout 10° C.
 103. The process of claim 100 wherein the temperature isabout 5° C.
 104. The process of claim 93 further comprising cooling thesolution of pravastatin sodium.
 105. The process of claim 93 furthercomprising cooling the solution of pravastatin sodium at a rate of about5.8° C. per hour to about 35° C. per hour.
 106. The process of claim 93further comprising cooling the solution of pravastatin sodium at a rateof about 2° C. per hour.
 107. The process of claim 93 whereinpravastatin sodium is at a concentration of about 0.05 to 0.5 M afterdilution with the protic solvent.
 108. The process of claim 93 furthercomprising heating the solution of pravastatin sodium to a temperatureabove 40° C. prior to the addition of the aprotic solvent.
 109. Theprocess of claim 108 wherein the temperature is about 60° C.
 110. Aprocess for preparing pravastatin sodium Form C comprising the steps of:(a) dissolving a solid form of pravastatin sodium in a protic solvent toform a solution; (b) diluting the solution of pravastatin sodium with anaprotic solvent; and (c) crystallizing the pravastatin sodium Form Cfrom the solution of pravastatin sodium.
 111. The process of claim 110wherein the protic solvent is water.
 112. The process of claim 110wherein the aprotic solvent is a polar aprotic solvent.
 113. The processof claim 112 wherein the polar aprotic solvent is a mixture of solventsselected from the group consisting of acetonitrile, acetone, and ethylacetate.
 114. The process of claim 112 wherein the polar aprotic solventis a mixture of acetonitrile and acetone.
 115. The process of claim 110wherein the aprotic solvent is a non-polar solvent.
 116. The process ofclaim 115 wherein the non-polar solvent is selected from the groupconsisting hexane, petroleum, ether and carbon tetra chloride.
 117. Theprocess of claim 110 wherein crystallizing pravastatin sodium isperformed at a temperature of between about −10° C. and 10° C.
 118. Theprocess of claim 117 wherein the temperature is about −10° C.
 119. Theprocess of claim 117 wherein the temperature is about 10° C.
 120. Theprocess of claim 117 wherein the temperature is about 5° C.
 121. Theprocess of claim 101 further comprising cooling the solution ofpravastatin sodium.
 122. The process of claim 110 further comprisingcooling the solution of pravastatin sodium at a rate of about 5.8° C.per hour to about 35° C. per hour.
 123. The process of claim 110 furthercomprising cooling the solution of pravastatin sodium at a rate of about2° C. per hour.
 124. The process of claim 110 wherein pravastatin sodiumis at a concentration of about 0.05 to 0.5 M after dilution with theprotic solvent.
 125. The process of claim 110 further comprising heatingthe solution of pravastatin sodium to a temperature above 40° C. priorto the addition of the aprotic solvent.
 126. The process of claim 125wherein the temperature is about 60° C.
 127. A process for preparingpravastatin sodium Form D comprising the steps of: (a) dissolving anysolid form of pravastatin sodium in a protic solvent to form a solution;(b) diluting the solution of pravastatin sodium with an aprotic solvent;and (c) crystallizing the pravastatin sodium Form D from the solution ofpravastatin sodium.
 128. The process of claim 127 wherein the proticsolvent is water.
 129. The process of claim 127 wherein the aproticsolvent is a polar aprotic solvent.
 130. The process of claim 129wherein the polar aprotic solvent is acetonitrile or acetone.
 131. Theprocess of claim 130 wherein the polar aprotic solvent is a mixture ofacetonitrile and acetone.
 132. The process of claim 127 wherein theaprotic solvent is a non-polar solvent.
 133. The process of claim 132wherein the non-polar solvent is selected from the group consistinghexane, petroleum, ether and carbon tetrachloride.
 134. The process ofclaim 127 wherein crystallizing pravastatin sodium is performed at atemperature of between about −10° C. and 10° C.
 135. The process ofclaim 134 wherein the temperature is about −10° C.
 136. The process ofclaim 134 wherein the temperature is about 10° C.
 137. The process ofclaim 134 wherein the temperature is about 5° C.
 138. The process ofclaim 127 further comprising cooling the solution of pravastatin sodium.139. The process of claim 127 further comprising cooling the solution ofpravastatin sodium at a rate of about 5.8° C. per hour to about 35° C.per hour.
 140. The process of claim 127 further comprising cooling thesolution of pravastatin sodium at a rate of about 2° C. per hour. 141.The process of claim 127 wherein pravastatin sodium is at aconcentration of about 0.05 to 0.5 M after dilution with the proticsolvent.
 142. The process of claim 127 further comprising heating thesolution of pravastatin sodium to a temperature above 40° C. prior tothe addition of the aprotic solvent.
 143. The process of claim 142wherein the temperature is about 60° C.
 144. A process for preparingpravastatin sodium Form E comprising the steps of: (a) dissolving anysolid form of pravastatin sodium in a protic solvent to form a solution;(b) diluting the solution of pravastatin sodium with an aprotic solvent;and (c) crystallizing the Form E pravastatin sodium from the solution ofpravastatin sodium.
 145. The process of claim 144 wherein the proticsolvent is a mixture of ethanol and water.
 146. The process of claim 144wherein the aprotic solvent is a polar aprotic solvent.
 147. The processof claim 144 wherein the polar aprotic solvent is a mixture of solventsselected from the group consisting of acetonitrile, acetone, and ethylacetate.
 148. The process of claim 144 wherein the aprotic solvent is anon-polar solvent.
 149. The process of claim 148 wherein the non-polarsolvent is ethyl acetate.
 150. The process of claim 149 wherein thenon-polar solvent is selected from the group consisting hexane,petroleum, ether and carbon tetrachloride.
 151. The process of claim 144wherein crystallizing pravastatin sodium is performed at a temperatureof between about −10° C. and 10° C.
 152. The process of claim 151wherein the temperature is about −10° C.
 153. The process of claim 151wherein the temperature is about 10° C.
 154. The process of claim 151wherein the temperature is about 5° C.
 155. The process of claim 144further comprising cooling the solution of pravastatin sodium.
 156. Theprocess of claim 144 further comprising cooling the solution ofpravastatin sodium at a rate of about 5.8° C. per hour to about 35° C.per hour.
 157. The process of claim 144 further comprising cooling thesolution of pravastatin sodium at a rate of about 2° C. per hour. 158.The process of claim 144 wherein pravastatin sodium is at aconcentration of about 0.05 to 0.5 M after dilution with the proticsolvent.
 159. The process of claim 144 further comprising heating thesolution of pravastatin sodium to a temperature above 40° C. prior tothe addition of the aprotic solvent.
 160. The process of claim 159wherein the temperature is about 60° C.
 161. A process for preparingpravastatin sodium Form F comprising the steps of: (a) dissolving anysolid form of pravastatin sodium in a protic solvent to form a solution;(b) diluting the solution of pravastatin sodium with an aprotic solvent;and (c) crystallizing the pravastatin sodium Form F from the solution ofpravastatin sodium.
 162. The process of claim 161 where the proticsolvent is water.
 163. The process of claim 161 wherein the aproticsolvent is a polar aprotic solvent.
 164. The process of claim 163wherein the polar aprotic solvent is acetonitrile or acetone.
 165. Theprocess of claim 164 wherein the polar aprotic solvent is a mixture ofsolvents selected from the group consisting of acetonitrile, acetone,and ethyl acetate.
 166. The process of claim 161 wherein the aproticsolvent is a non-polar solvent.
 167. The process of claim 166 whereinthe non-polar solvent is selected from the group consisting hexane,petroleum, ether and carbon tetrachloride.
 168. The process of claim 161wherein crystallizing pravastatin sodium is performed at a temperatureof between about −10° C. and 10° C.
 169. The process of claim 166wherein the temperature is about −10° C.
 170. The process of claim 166wherein the temperature is about 10° C.
 171. The process of claim 166wherein the temperature is about 5° C.
 172. The process of claim 161further comprising cooling the solution of pravastatin sodium.
 173. Theprocess of claim 161 further comprising cooling the solution ofpravastatin sodium at a rate of about 5.8° C. per hour to about 35° C.per hour.
 174. The process of claim 161 further comprising cooling thesolution of pravastatin sodium at a rate of about 2° C. per hour. 175.The process of claim 161 wherein pravastatin sodium is at aconcentration of about 0.05 to 0.5 M after dilution with the proticsolvent.
 176. The process of claim 161 further comprising heating thesolution of pravastatin sodium to a temperature above 40° C. prior tothe addition of the aprotic solvent.
 177. The process of claim 176wherein the temperature is about 60° C.
 178. A process for preparingpravastatin sodium Form G comprising exposing pravastatin Form F to arelative humidity of between about 40 to about 80%.
 179. A process forcrystallizing pravastatin sodium as polymorph Form A, comprisingexposing polymorph Form D or polymorph Form F to the vapors of ethanolfor three weeks.
 180. A process for crystallizing pravastatin sodium aspolymorph Form H, comprising exposing polymorph Form D or polymorph FormF to the vapors of ethanol for three weeks.
 181. A process forcrystallizing pravastatin sodium as polymorph Form H1, comprisingsuspending polymorph Form D in methanol.
 182. A process forcrystallizing pravastatin sodium as polymorph Form I, comprisingexposing polymorph Form D or polymorph Form F to the vapors ofisopropanol.
 183. A process for crystallizing pravastatin sodium aspolymorph Form J, comprising exposing polymorph Form D or polymorph FormF to the vapors of butanol.
 184. A process for crystallizing pravastatinsodium as a polymorph Form K, comprising suspending pravastatin in asolvent.
 185. The process of claim 184 wherein the solvent is selectedfrom the group consisting of ethanol, isopropyl alcohol and butanol.186. A process for crystallizing pravastatin Form D and hydrates thereofby heating pravastatin to a temperature above room temperature.
 187. Theprocess of claim 186 wherein pravastatin is a crystalline pravastatinform.
 188. The process of claim 186 wherein the crystalline pravastatinform is Form D, Form A, Form C, Form D, Form E, Form G, Form H or FormH1.
 189. The process of claim 186 wherein pravastatin is amorphouspravastatin.
 190. The process of claim 189 wherein the amorphouspravastatin is Form F.
 191. The process of claim 186 wherein thetemperature is 120° C.
 192. The process of claim 186 wherein the heatingis performed for 2 hours.
 193. A process for crystallizing pravastatinForm C by incubating pravastatin at 100% relative humidity.
 194. Theprocess of claim 193 wherein the incubation is performed for 1 week.195. Pravastatin sodium with water content of at least 30%. 196.Pravastatin sodium with a water content of at least 20%.
 197. A processfor preparing pravastatin sodium Form L comprising the steps of: (a)dissolving any solid form of pravastatin sodium in a protic solvent toform a solution; (b) diluting the solution of pravastatin sodium with anaprotic solvent; and (c) crystallizing the pravastatin sodium Form Lfrom the solution of pravastatin sodium.
 198. The process of claim 197wherein the protic solvent is water.
 199. The process of claim 197wherein the aprotic solvent is acetone.
 200. The process of claim 197further comprising cooling a solution of pravastatin sodium at a rate ofabout 2° C.h⁻¹.
 201. A process for preparing pravastatin sodium Form Dcomprising the steps of: (a) dissolving any solid form of pravastatinsodium in a protic solvent to form a solution; (b) diluting the solutionof pravastatin sodium with an aprotic solvent; (c) crystallizing thepravastatin sodium Form L from the solution of pravastatin sodium; and(d) drying pravastatin sodium Form L to produce Form D.
 202. The processof claim 201 wherein drying pravastatin Form L comprises gradual heatingto about 60° C.
 203. The process of claim 201 further comprising coolinga solution of pravastatin sodium at a rate of about 2° C.h⁻¹.